The causes of Alcohol Use Disorder (AUD) are complex, with genetic and environmental contributions. Several behavioral phenotypes are closely associated with and precede AUD in the life course. We propose to investigate genetic susceptibility, gene-gene, and gene-environment interactions for the development of AUD. We will focus on three major neurotransmitter systems implicated in the neural excitation-inhibition balance, serotonergic, dopaminergic and GABAergic pathways. Homeostatic plasticity driven by this balance is necessary for adequate information transfer in the brain. We will perform association tests between these genes and behavioral phenotypes that measure under-control and negative affectivity, two of the most clearly identified behavioral endophenotypes that increase risk for transitioning from experimentation into problem use, as well as with phenotypes that measure progression into AUD severity, the lifetime alcohol problems score, and diagnosis, with age of onset as a covariate, and a longitudinal model designed by Dr. Jester that measures the number of alcohol symptoms (DSM-IV) over time in the parents. For gene-environment interactions we will consider a retrospective measure of childhood maltreatment. The research will be conducted using data from the ongoing Michigan Longitudinal Study (MLS), a prospective community ascertained study of 466 families at varying risk for alcoholism that has been ongoing for over 20 years (954 parents and 1003 offspring), with assessments at 3-year intervals and yearly between ages 11 and 17. We have obtained funding from the University of Michigan to genotype the 528 most informative individuals for 1536 SNPs (1430 SNPs from 132 addiction-relevant candidate genes and 106 genomic controls SNPs) from an "addiction panel" designed by David Goldman (NIAAA), using the Illumina GoldenGate technology which has been used nationwide to analyze addiction-related traits. Because the panel also includes SNPs to measure ethnic stratification, it will also alleviate concerns about heterogeneity. Specific aims for this proposal are: 1) Identify genetic polymorphisms from the serotonin, dopamine and GABA pathways involved in behavioral traits (behavioral under-control and negative affectivity traits) that increase risk for alcohol used disorders (AUDs). 2) From these same set of genes identify genetic variants that influence progression into AUD severity. 3) Determine if childhood abuse interacts with genetic variants associated with progression into AUD severity. Genetic variation in these genes may influence the neural excitation-inhibition balance and in turn may impact behavioral traits that increase risk to develop AUDs and interact with environmental factors such as childhood abuse. The PI will gain experience in the statistical approaches of gene-environment and gene-gene interactions, longitudinal models and further advance her understanding of behavioral risk factors to develop AUDs. The PI will be able to add the genetic expertise to the MLS research group. PUBLIC HEALTH RELEVANCE: This study intends to understand the genetic and environmental risk and protective factors involved in the etiology of alcohol use disorders. The identification of these risk or protective factors will help to better screen vulnerable subjects, improve risk assessment, delineate preventive interventions and facilitate appropriate treatment.